Insulin-like growth factor II inhibits glucose-induced insulin exocytosis.
We have investigated the effect of IGF-II on glucose-induced insulin release in the pancreatic beta-cell. Introduction of IGF-II during perifusion of the cells with 20 mM glucose abolished glucose-induced insulin release. Concomitant addition of IGF-II with 20 mM glucose caused a complete inhibition of insulin release. In addition, IGF-II inhibited Ca(2+)-induced insulin release from electropermeabilized pancreatic beta-cells. IGF-II had no effect on K(+)-or tolbutamide-induced insulin release. However, IGF-II could suppress K(+)-stimulated insulin release when cells were pretreated with the protein phosphatase inhibitor okadaic acid. The inhibitory effect of IGF-II on insulin release was not associated with significant changes in membrane potential, activity of the voltage-gated L-type Ca(2+)-channel or cytoplasmic free Ca2+ concentration. Pretreatment of the cells with pertussis toxin or the phorbol ester TPA abolished the inhibitory action of IGF-II on insulin release. Hence, the molecular mechanism whereby activation of the IGF-II/M6P receptor by IGF-II inhibits glucose-stimulated insulin exocytosis in the pancreatic beta-cell involves pertussis toxin-sensitive G proteins and is dependent on PKC activity.
Zhang
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Department of Molecular Medicine, Rolf Luft Center for Diabetes Research, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
Berggren
P O
PO
Larsson
O
O
Hall
K
K
Tally
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M
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D019319:Okadaic Acid / Q000494:pharmacology; D037342:Pertussis Toxin; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D011188:Potassium / Q000494:pharmacology; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D014044:Tolbutamide / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D015220:Calcium Channels; D004791:Enzyme Inhibitors; D007328:Insulin; D017527:Receptor, IGF Type 2; D010566:Virulence Factors, Bordetella; D019319:Okadaic Acid; D007335:Insulin-Like Growth Factor II; D014044:Tolbutamide; D037342:Pertussis Toxin; D010749:Phosphoprotein Phosphatases; D019204:GTP-Binding Proteins; D005947:Glucose; D011188:Potassium; D002118:Calcium